Carbene porphyrins and carbene porphyrinoids, methods of preparation and uses thereof

ABSTRACT

The present invention includes novel N-heterocyclic carbene substituted porphyrins and porphyrinoids. The invention also includes complexes of metals and N-heterocyclic carbene substituted porphyrins and porphyrinoids. The invention further includes N-heterocyclic carbene substituted porphyrins and porphyrinoids. and metal complexes of N-heterocyclic carbene substituted porphyrins and porphyrinoids that also includes a targeting moiety or group. The compositions of the present invention are useful in the fields of diagnosis and treatment of many medical ailments.

TECHNICAL FIELD OF THE INVENTION

[0001] The present invention relates to novel compositions of matter.The present invention more particularly relates to ligands, complexes ofthe ligands with metals to form ligand-metal complexes, processes forpreparation of the ligands and ligand-metal complexes and uses thereof.

BACKGROUND OF THE INVENTION

[0002] Porphyrins and related tetrapyrrolic macrocycles have applicationin various medical procedures for the diagnosis and treatment ofdisease.

[0003] Magnetic Resonance Imaging (MRI) is a process in which aparticular object to be viewed is exposed to a radio frequency while inthe presence of a varying magnetic field. In general, MRI utilizescontrast agents to produce cross-sectional images for medical diagnosis.The use of contrast agents allows one to differentiate the target tissueof interest from the surrounding tissue in the image. The use ofcontrast agents with MRI, however, suffers from several limitations. Forexample, one major limitation of the use of certain contrast agents isthe disassociation of the metal from the metal complex of the contrastagent, which can leave toxic levels of metals within the body of anpatient.

[0004] Positron Emission Tomography (PET) is a type of tomographyproduced by the detection of gamma rays emitted from tissues after theadministrations of a natural biochemical substance into whichpositron-emitting isotopes have been incorporated. A major limitation ofthe use of certain contrast agents with PET is the disassociation of theradioactive isotopes from the agent, which can leave toxic levels ofradioactive elements within the body of an patient.

[0005] Porphyrins and related tetrapyrrolic macrocycles also haveapplication in the field of Photodynamic Therapy (PDT). PDT is atechnique that utilizes photosensitive compounds that have a selectiveaffinity for diseased tissue and which accumulate in diseased tissue toa greater extent than in normal tissue. PDT involves the localization ofa photosensitizing agent in or near a diseased target tissue within thebody. The photosensitive compound, upon illumination and in the presenceof oxygen, produces cytotoxic species of oxygen such as singlet oxygenor oxygen radicals, which destroy the diseased target tissue. The PDTtechnique provides a greater degree of selectivity or specificity notcurrently achievable with current methods of chemotherapy.

[0006] Heterocyclic carbenes have been found to be useful as complexingligands for a wide variety of metals to produce correspondingligand-metal complexes having good thermal and chemical stability.

[0007] The synthesis of transition metal complexes ofimidazol-2-ylidenes, also known as N-heterocyclic carbenes, was firstpioneered by Ofele and Wanzlick in 1968 and is a very active area ofresearch today. The synthesis of free isolable N-heterocyclic carbenesand their complexation with transition metals was first reported byArduengo in 1991. It is not always convenient, however, to synthesizecomplexes from free carbenes and transition metals. A recent advance isthe use of silver bis(carbene) complexes as carbene transfer reagents.

[0008] A process for the preparation of heterocyclic carbenes isdescribed in U.S. Pat. No. 6,025,496 to Hermann et al.

[0009] Therefore, the needs exists in the art to develop improvedligands and ligand-metal complexes for diagnostic and therapeuticapplications.

SUMMARY OF THE INVENTION

[0010] The present invention, in one embodiment, provides a compositionof matter comprising a N-heterocyclic carbene substituted porphyrins.

[0011] The present invention, in another embodiment, provides acomposition of matter comprising a N-heterocyclic carbene substitutedporphyrinoids.

[0012] The present invention, in another embodiment, further provides acomplex comprising a N-heterocyclic carbene substituted porphyrin ligandand a metal bonded to said ligand.

[0013] The present invention, in another embodiment, further provides acomplex comprising a N-heterocyclic carbene substituted porphyrinoidligand and a metal bonded to said ligand.

[0014] The present invention, in another embodiment, further provides amethod for preparing N-heterocyclic carbene substituted porphyrins.

[0015] The present invention, in another embodiment, further provides amethod for preparing N-heterocyclic carbene substituted porphyrinoids.

[0016] The present invention, in another embodiment, further includes amethod for providing a complex comprising a N-heterocyclic carbenesubstituted porphyrin ligand and a metal bonded to said ligand.

[0017] The present invention, in another embodiment, further provides amethod for preparing a complex comprising a N-heterocyclic carbenesubstituted porphyrinoid ligand and a metal bonded to said ligand.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0018] The present invention provides novel macrocycles suitable fordetecting (diagnosing) and treating target tissues, cells and pathogens.The compositions of the present invention possess novel chelatingproperties and cavity sizes, which enable them to stabilize metals in arange of typical and a typical oxidation states and coordinationgeometries. The compositions of the present invention find particularapplication in medical applications, such as Magnetic Resonance Imaging(MRI), Positron Emission Tomography (PET), Photodynamic Therapy (PDT),although the compositions have a wide variety of other applications.

[0019] In on embodiment, the present invention relates to N-heterocycliccarbene substituted porphyrins. That is, the compositions of the presentinvention are substituted porphyrins having at least one pyrrole ring ofthe porphyrin ring replaced by a N-heterocyclic carbene group. In otherembodiments of the present invention, in addition to having at least onepyrrole group of the porphyrin ring replaced with a N-heterocycliccarbene group, at least one of the pyrrole groups of the porphyrin ringmay also be replaced with a pyridine ring.

[0020] As those having ordinary skill in the art know, the term“porphyrin” refers to any of several physiologically activenitrogen-containing compounds. In general, a porphyrin compound includesfour pyrrole rings, each ring containing a nitrogen atom and where twoof the pyrrole rings also include replaceable hydrogen atoms. Aporphyrin may be generally represented by the following formula:

[0021] The synthesis of porphyrin isomers is known, where the nitrogenatom of one of the pyrrole rings that binds to a central metal atom toform a metal complex is replaced with a carbon atom. These porphyrinisomers, referred to as carbaporphyrins, N-confused porphyrins, orinverted porphyrins, may be represented by the following formula:

[0022] N-confused porphyrins as shown in Formula II, above, have amultivalent nature as a metal ligand and are known to complex with metalatoms in the +2 and +3 oxidation states to form neutral square planarcomplexes, as shown in the following formulas:

[0023] Doubly N-confused porphyrins may also be synthesized and are ableto form metal complexes with metals in the +3 oxidation state, as shownby the following formula:

[0024] The N-heterocyclic carbene substituted porphyrins andporphyrinoids of the present invention may be broadly represented by thefollowing formulas:

[0025] where formulas VI and VII, A-D may be the same or different andmay be selected from one of the following formulas, with the provisothat at least one of A-D is N-heterocyclic carbene:

[0026] where R₁-R₁₁ may be hydrogen and organic groups including alkyl,cyclo alkyl, substituted cycloalkyl, alkenyl, cycloalkenyl, substitutedcycloalkenyl, alkynyl, aryl, substituted aryl, arylalkyl, alkylaryl, andalkoxy, where each group preferably contains from 1 carbon atom to about10 carbon atoms, preferably containing from 1 carbon atom to about 6carbon atoms;

[0027] where x may be CR₁₂ or CR₁₃R₁₄, where R₁₂, R₁₃ and R₁₄ may behydrogen and organic groups including alkyl, cyclo alkyl, substitutedcycloalkyl, alkenyl, cycloalkenyl, substitute cycloalkenyl, alkynyl,aryl, substituted aryl, arylalkyl, alkylaryl, and alkoxy, where eachgroup preferably contains from 1 carbon atom to about 10 carbon atoms,preferably containing from 1 carbon atom to about 6 carbon atoms.

[0028] The N-heterocyclic carbene substituted expanded porphyrins andexpanded porphyrinoids of the present invention may be broadlyrepresented by the following formulas:

[0029] where formulas XI and XII, A-D may be the same or different andmay be selected from one of the following formulas, with the provisothat at least one of A-D is N-heterocyclic carbene:

[0030] where R₁-R₁₁ may be hydrogen and organic groups including alkyl,cyclo alkyl, substituted cycloalkyl, alkenyl, cycloalkenyl, substitutedcycloalkenyl, alkynyl, aryl, substituted aryl, arylalkyl, alkylaryl, andalkoxy, where each group preferably contains from 1 carbon atom to about10 carbon atoms, preferably containing from 1 carbon atom to about 6carbon atoms;

[0031] where x may be CR₁₂ or CR₁₃R₁₄, where R₁₂, R₁₃ and R₁₄ may behydrogen and organic groups including alkyl, cyclo alkyl, substitutedcycloalkyl, alkenyl, cycloalkenyl, substitute cycloalkenyl, alkynyl,aryl, substituted aryl, arylalkyl, alkylaryl, and alkoxy, where eachgroup preferably contains from 1 carbon atom to about 10 carbon atoms,preferably containing from 1 carbon atom to about 6 carbon atoms; andwhere Ay, By, Cy and Dy is 1 or greater, with the proviso that at leastone of Ay, By, Cy and Dy is at least 2.

[0032] The following examples are set forth to describe theN-heterocyclic substituted carbene porphyrin and porphyrinoidcompositions of the present invention in further detail. The examplesare intended to be illustrative, and should not be construed as limitingthe scope of the present invention in any manner.

[0033] In one embodiment, at least one pyrrole ring of the porphyrin isreplaced with a N-heterocyclic carbene group. The composition of thisembodiment may be represented by any one of the following formulas:

[0034] In another embodiment, two of the pyrrole rings of the porphyrincompound have been replaced with N-heterocyclic carbene groups. Thecompounds having two pyrrole rings replaced with N-heterocyclic carbenegroups may be represented by any one of the following formulas:

[0035] In another embodiment, three pyrrole rings of the porphyrincompound have been replaced with N-heterocyclic carbene groups. Thecompounds have three N-heterocyclic carbene groups may be represented bythe following formula:

[0036] In another embodiment, four pyrrole rings of the porphyrincompound have been replaced with N-heterocyclic carbene groups. Thecompositions having four pyrrole rings of the porphyrin compound havebeen replaced with N-heterocyclic carbene groups may be represented bythe following formula:

[0037] In another embodiment, the present invention providescompositions wherein at least one of the pyrrole rings of the porphyrincompound is replaced with a N-heterocyclic carbene group and at leastone other pyrrole rings is replaced with a pyridine ring. Thecompositions having at least one of the pyrrole rings of the porphyrincompound is replaced with a N-heterocyclic carbene group and at leastone other pyrrole ring is replaced with a pyridine ring may berepresented by any one of the following formulas:

[0038] While the present invention has been described with respect tothe substitution of porphyrins with at least one N-heterocyclic carbenegroup, the compositions and processes described herein also encompassother tetrapyrrolic macrocycles, such as the larger aromaticpyrrole-containing systems, referred to as “expanded porphyrins”.

[0039] The term expanded porphyrin and expanded porphyrinoids refer tothose large aromatic pyrrole-containing systems that generally containmore than four rings that constitute the macrocycle. As for theporphyrin systems, at least one pyrrole ring of an expanded porphyrin orexpanded porphyrinoid can be replaced with a N-heterocyclic carbenegroup to form a N-heterocyclic carbene expanded porphyrin or aN-heterocyclic carbene substituted expanded porphyrinoid.

[0040] In one embodiment, at least one pyrrole ring of the expandedporphyrin sapphyrin may be replaced by a N-heterocylic carbene group.Sapphyrin is represented by the following formula:

[0041] Compounds of the present invention having at least one pyrrolering of the expanded porphyrin sapphyrin replaced by a N-heterocyliccarbene group are represented by the following formulas:

[0042] In another embodiment, the present invention providescompositions having at least two pyrrole rings of the expanded porphyrinsapphyrin replaced with N-heterocyclic carbene groups. Compounds of thepresent invention having at least two pyrrole rings of the expandedporphyrin sapphyrin replaced by N-heterocylic carbene groups arerepresented by the following formulas:

[0043] In another preferred embodiment, at least one pyrrole ring of theexpanded porphyrin pentaphyrin is replaced by a N-heterocylic carbenegroup. The expanded porphyrin pentaphyrin is represented by thefollowing formula:

[0044] In one embodiment, at least one pyrrole ring of the expandedporphyrin pentaphyrin has been replaced with a N-heterocyclic carbenegroup. Compositions of the present invention having at least one pyrrolering of the expanded porphyrin pentaphyrin has been replaced with aN-heterocyclic carbene group are represented by the following formulas:

[0045] In another embodiment, at least two pyrrole rings of the expandedporphyrin pentaphyrin has been replaced with a N-heterocyclic carbenegroups. Compositions of the present invention having at least twopyrrole rings of the expanded porphyrin pentaphyrin has been replacedwith a N-heterocyclic carbene groups is represented by the followingformula:

[0046] In another preferred embodiment, at least one pyrrole ring of theexpanded porphyrin hexaphyrin is replaced by a N-heterocylic carbenegroup. Hexaphyrin is represented by the following formula:

[0047] In one embodiment, at least one pyrrole ring of the expandedporphyrin hexaphyrin is replaced by a N-heterocyclic carbene group.Compositions of the present invention at least one pyrrole ring of theexpanded porphyrin hexaphyrin is replaced by a N-heterocyclic carbenegroup are represented by the following formula:

[0048] In another embodiment, at least two pyrrole rings of the expandedporphyrin hexaphyrin is replaced by N-heterocyclic carbene group.Compositions of the present invention at least two pyrrole rings of theexpanded porphyrin hexaphyrin are replaced by N-heterocyclic carbenegroups are represented by the following formulas:

[0049] In another embodiment, at least three pyrrole rings of theexpanded porphyrin hexaphyrin are replaced by N-heterocyclic carbenegroups. Compositions of the present invention at least three pyrrolerings of the expanded porphyrin hexaphyrin are replaced byN-heterocyclic carbene groups are represented by the following formula:

[0050] While the present invention has been illustrated in furtherdetail with reference to tetrapyrrolic porphyrin and the expandedporphyrins sapphryin, pentaphyrin and hexaphyrin, it should be notedthat the present invention is not limited to those expanded porphyrinsdescribed herein. The present invention, therefore, includes otherexpanded porphyrins in which at least one pyrrole ring is replaced byN-heterocyclic carbene groups.

[0051] The N-heterocyclic carbene substituted porphyrins andN-heterocyclic carbene substituted porphyrinoids of the presentinvention are useful as ligands to form ligand-metal complexes with aselected or desired metal atom or atoms.

[0052] The metal complexes of the present invention include aN-heterocyclic carbene substituted porphyrin or N-heterocyclic carbenesubstituted porphyrinoid and at least one metal atom bonded to theN-heterocyclic carbene substituted porphyrin or N-heterocyclic carbenesubstituted porphyrinoids. The metal complexes of this embodiment may bebroadly represented by the following formulas:

[0053] where for formulas XXXXVI and XXXXVII, A-D may be the same ordifferent and may be selected from one of the following formulas, withthe proviso that at least one of A-D is N-heterocyclic carbene:

[0054] where R₁-R₁₁ may be hydrogen and organic groups including alkyl,cyclo alkyl, substituted cycloalkyl, alkenyl, cycloalkenyl, substitutedcycloalkenyl, alkynyl, aryl, substituted aryl, arylalkyl, alkylaryl, andalkoxy, where each group preferably contains from 1 carbon atom to about10 carbon atoms, preferably containing from 1 carbon atom to about 6carbon atoms;

[0055] where x may be CR₁₂ or CR₁₃R₁₄, where R₁₂, R₁₃ and R₁₄ may behydrogen and organic groups including alkyl, cyclo alkyl, substitutedcycloalkyl, alkenyl, cycloalkenyl, substitute cycloalkenyl, alkynyl,aryl, substituted aryl, arylalkyl, alkylaryl, and alkoxy, where eachgroup preferably contains from 1 carbon atom to about 10 carbon atoms,preferably containing from 1 carbon atom to about 6 carbon atoms; andwhere M is a metal.

[0056] The metal complexes of this embodiment, which in clued at leastone metal atom bonded to a N-heterocyclic carbene substituted expandedporphyrin or expanded porphyrinoids may be broadly represented by thefollowing formulas:

[0057] where formulas XXXXVIII and XXXXIX, A-D may be the same ordifferent and may be selected from one of the following formulas, withthe proviso that at least one of A-D is N-heterocyclic carbene:

[0058] where R₁-R₁₁ may be hydrogen and organic groups including alkyl,cyclo alkyl, substituted cycloalkyl, alkenyl, cycloalkenyl, substitutedcycloalkenyl, alkynyl, aryl, substituted aryl, arylalkyl, alkylaryl, andalkoxy, where each group preferably contains from 1 carbon atom to about10 carbon atoms, preferably containing from 1 carbon atom to about 6carbon atoms;

[0059] where x may be CR₁₂ or CR₁₃R₁₄, where R₁₂, R₁₃ and R₁₄ may behydrogen and organic groups including alkyl, cyclo alkyl, substitutedcycloalkyl, alkenyl, cycloalkenyl, substitute cycloalkenyl, alkynyl,aryl, substituted aryl, arylalkyl, alkylaryl, and alkoxy, where eachgroup preferably contains from 1 carbon atom to about 10 carbon atoms,preferably containing from 1 carbon atom to about 6 carbon atoms; andwhere Ay, By, Cy and Dy is 1 or greater, with the proviso that at leastone of Ay, By, Cy and Dy is at least 2; and where M is a metal.

[0060] Metal M may be selected from all of the main group metals andtransition metals may to be complexed with the N-heterocyclic carbenesubstituted porphyrin and porphyrinoid ligands to form metal complexes.Additionally, isotopes of the main group metals and transition metalsmay be complexed with the ligands of the present invention to providesmetal complexes.

[0061] While the known doubly N-confused porphyrins form neutral metalcomplexes with metals in +2 and +3 oxidation states, the carbeneporphyrins, carbene porphyrinoids, expanded carbeneporphyrins andexpanded carbeneporphyrinoids have the capability of forming neutralmetal complexes with metals in the 0, +1, +2, +3, +4, and +5 oxidationstates. Because of the strong complexing ability of N-heterocycliccarbenes, the compositions of the present invention, thecarbeneporphyrins and expanded carbeneporphyrins, bind more strongly tothe central metal atom in comparison to porphyrins and confusedporphyrins without substitution with N-heterocyclic carbene groups.

[0062] The N-heterocyclic carbene porphyrins, including theN-heterocyclic carbene porphyrinoids, and the expanded N-heterocycliccarbene porphyrins, including the expanded N-heterocyclic carbeneporphyrinoids, of the present invention may be complexed with metalatoms to form ligand-metal complexes. Virtually of the of the main groupmetals and transition metals may be complexed with the N-heterocycliccarbene porphyrins, including the N-heterocyclic carbene porphyrinoids,and the expanded N-heterocyclic carbene porphyrins, including theexpanded N-heterocyclic carbene porphyrinoids, of the present inventionto form ligand-metal complexes.

[0063] Suitable metal atoms, M, that may be complexed with theN-heterocyclic carbene porphyrins and N-heterocyclic carbeneporphyrinoids of the present invention include, but are not limited to,all group IIA metals, group IIA metals, group IIIA metals, group IVAmetals, group VA metals, group VIA metals, group VIIA metals, and groupVIIIA metals. The group IVB metals Si, Ge, SN and Pb may be complexedwith the N-heterocyclic carbene porphyrins and N-heterocyclic carbeneporphyrinoids to form ligand-metal complexes. The group VB metals P, As,Sb and Bi may be complexed with N-heterocyclic carbene porphyrins andN-heterocyclic carbene porphyrinoids to form ligand-metal complexes. Thegroup VIB metals Te and Po may be complexed with N-heterocyclic carbeneporphyrins and N-heterocyclic carbene porphyrinoids to form ligand-metalcomplexes. The group VIIB metal At may be complexed with N-heterocycliccarbene porphyrins and N-heterocyclic carbene porphyrinoids to formligand-metal complexes. Additionally, the lanthanides and the actinidesmay be complexed with the N-heterocyclic carbene porphyrins andN-heterocyclic carbene porphyrinoids of the present invention to formligand-metal complexes.

[0064] Preferably, the metals that may be used to form metal complexeswith the ligands include those metals that have particular applicationin MRI, PET and PDT. These metals include, but are not limited to,Be(II), Mg(II), Ca(II), Sr(II), Ba(II), B(III), Al(III), Ga(III),In(III), Cr(O), Fe(O), Ni(O), Mo(O), Ru(O), Pd(O), Pt(O), Re(I), Cr(I),Mn(I), Fe(I), Co(I), Ni(I), Cu(I), Rh(I), Ag(I), Re(I), Ir(I), Au(I),V(I), Cr(II), Fe(II), Co(II), Ir(III), Ti(IV), V(IV), Zr(IV), Nb(IV),Hf(IV), Ta(IV), Mo(IV), W(VI), Re(VII), La(II), La(III), Nd(III),Sm(II), Er(III), Sm(II) and Yb(II). Suitable examples of these metalshaving particular application in MRI and are, therefore, useful in thepresent invention include, but are not limited to, Fe(III), Mg(II),Mn(II), and Gd(III). More preferably, Gd(III) will be used to formligand-metal complexes that find particular use in MRI applications.Useful radioisooptes that can be complexed with the N-heterocyliccarbene substituted porphyrins and porphyrinods in clued, but are notlimited to, ⁶⁷Cu, ¹⁰⁵Rh, ¹¹¹Ag, ¹¹⁷Sn, ¹⁸⁶Re, ¹⁴⁹Pm, ¹⁵³Sm, ¹⁶⁶Ho and¹⁷⁷Lu. ¹¹¹Ag is a preferred radioisotope that can be complexed with theN-heterocyclic carbenes substituted ligands of the present invention.

[0065] The present invention also provides processes for the preparationfor of the N-heterocyclic carbene substituted porphyrins andN-heterocyclic carbene substituted porphyrinoids of the presentinvention, including the preparation of N-heterocyclic carbenesubstituted expanded porphyrins and N-heterocyclic carbene substitutedexpanded porphyrinoids.

[0066] The present invention further provides a process for thepreparation of a complex of the ligands of the present invention with adesired metal to produce a ligand-metal complex.

[0067] Preparation of N-Heterocyclic Carbene Porphyrins AndPorphyrinoids

[0068] The following examples are set forth to describe the preparationof the compositions of the present invention in further detail and toillustrate the methods of the present invention. However, the examplesshould not be construed as limiting the present invention in any manner.

[0069] In the following synthetic procedures the synthesis of theligands of the present invention is described. However, ligands can besynthesized with various functional groups on the exterior of the ringsin order to give the overall complex sufficient solubility,lipophilicity and targeting properties. Pyrroles and imidazoles serve asthe fundamental building blocks in the procedures discussed below.

[0070] Synthesis of Monocarbeneporphyrin

[0071] Below is a reaction scheme for the synthesis of monoN-heterocyclic carbene substituted porphyrin:

[0072] Synthesis of Dicarbeneporphyrinoids

[0073] Below is a reaction scheme for the synthesis of di N-heterocycliccarbene substituted porphyrinoids:

[0074] Synthesis of Tricarbeneporphyrinoids

[0075] Below is a reaction scheme for the synthesis oftricarbeneporphyrinoids and ligand-metal complexes oftricarbeneporphyrinoids and a metal:

[0076] Synthesis of Tetracarbeneporphyrinoids Below is a reaction schemefor the synthesis of tetracarbeneporphyrinoids and ligand-metalcomplexes of tetracarbeneporphyrinoids and a metal:

[0077] Synthesis of Carbene Corrole Porphyrins

[0078] Below is a reaction scheme for the synthesis of carbene corroleporphyrins and ligand-metal complexes of carbene corrole porphyrins anda metal:

[0079] Synthesis of Expanded Monocarbenepentaphyrin Below is a reactionscheme for the synthesis of mono N-heterocylic carbene substitutedexpanded porphyrin:

[0080] Synthesis of Dicarbenepentaphyrin Below is a reaction scheme forthe synthesis of di-N-heterocylic carbene substituted expandedporphyrin:

[0081] It should be noted that the term “N-heterocyclic carbeneporphyrin” refers to porphyrins that have at least one pyrrole groupreplaced by a N-heterocyclic carbene and having unsaturated bondslinking the groups of the ring together or a mixture of saturated andunsaturated bonds linking the group of the ring together. The term“N-heterocyclic carbene porphyrinoid” refers to porphyrins that have atleast one pyrrole group replaced by a N-heterocyclic carbene group andhaving saturated bonds linking the groups of the ring together.

[0082] In other embodiments, the N-heterocyclic carbene substitutedporphyrins and porphyrinoids and metal complexes of the N-heterocycliccarbene substituted porphyrins and porphyrinoids may be further linkedor bonded to a targeting moiety via a linker group. The targeting moietymay be selected to be specific to a receptor or protein located on atarget tissue or cell. The targeting moiety further enables theligand-metal complexes of the present invention to target specifictissue for diagnosis and treatment. In an alternative embodiment, thelinker group and targeting moiety are dissociative, which enables theligand-metal complex to diffuse out of the target tissue or cells and beremoved from the patient's body.

[0083] Preparation of N-Heterocyclic Carbene Porphyrins With TargetingMoiety

[0084] Below are reaction schemes for the synthesis of N-heterocycliccarbene substituted porphyrins having a targeting moiety bonded thereto:

[0085] The targeting moiety is bonded to the N-heterocyclic carbenesubstituted porphyrin via a linker group. The linker group can be anyorganic group including, for example, organic radical groups andpolymers. Suitable organic groups include alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl,substituted aryl, arylalkyl, alkylaryl, alkoxy, amines, amides, andpolyethers. The targeting moiety can be selected in order to optimizethe solubility and lipophilciy of t

[0086] The N-heterocyclic carbene substituted ligands of the presentinvention, including the N-heterocyclic carbene substituted porphyrinsand porphyrinoids, possess cavity sizes and chelating properties thatenable the ligands to bind metal atoms more stringly thatn thosemacrocyles known in the prior art. The ability of the ligands of thepresent invention to bind more strongly to the metal atoms helpsovercome the problems of dissociation of metal from the ligand while themetal complex is in a patient's body. As such, the ligands and metalcomplexes of the invention can be utilized as radioimaging agents andtherapeutic radiopharmaceuticals for treating, for example, cancer. Themetal complexes of the present invention can be used to recognizetumor-associated antigens and tumor specific antigens to deliver atherapeutic and cytotoxic agent to cancerous tissue and cells, whileminimizing exposure of the cytotoxic agents to non-cancerous, healthytissue and cells. Antibodies such as, for example, monoclonal antibodiesthat recognize tumor associated antigen or tumor specific antigen, arecomplexed with strepravidin and infused into a patient. The antibodyrecognizes the tumor associated antigen and associates with is, therebylocalizing the streptavidin in the tumor tissue. Subsequently, the metalcomplexes of N-heterocyclic carbene substituted porphyrins orporphyrinoid, which have biotin bound thereto, are infused into thepatient. The streptavidin binds the biotin and localizes theradionucleotide at the tumor tissue.

[0087] Based on the foregoing disclosure, it is therefore demonstratedthat the objects of the present invention are accomplished by theN-heterocyclic carbene porphyrins and porphyrinoids described andprocesses for installation described herein. It should be appreciatedthat the present invention is not limited to the specific embodimentsdescribed above, but includes variations, modifications and equivalentembodiments.

We claim:
 1. A composition of matter comprising a N-heterocylic carbenesubstituted porphyrin.
 2. The composition of claim 1, wherein saidN-heterocylic carbene substituted porphyrin has the following generalformula:

wherein A-D may be the same or different and may be selected from one ofthe following formulas:

wherein R₁-R₁₁ may be hydrogen and organic groups including alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, cycloalkenyl, substitutedcycloalkenyl, alkynyl, aryl, substituted aryl, arylalkyl, alkylaryl, andalkoxy, where each group preferably contains from 1 carbon atom to about10 carbon atoms, preferably containing from 1 carbon atom to about 6carbon atoms; and wherein x may be CR₁₂ or CR₁₃R₁₄, where R₁₂, R₁₃ andR₁₄ may be hydrogen and organic groups including alkyl, cyclo alkyl,substituted cycloalkyl, alkenyl, cycloalkenyl, substitute cycloalkenyl,alkynyl, aryl, substituted aryl, arylalkyl, alkylaryl, and alkoxy. 3.The composition of matter of claim 2, wherein each of R₁-R₁₄ containsfrom 1 carbon atom to about 10 carbon atoms.
 4. The composition of claim3, wherein each of R₁-R₁₄ contains from 1 carbon atom to about 6 carbonatoms.
 5. The composition of matter of claim 1, wherein saidN-heterocylic carbene substituted porphyrin has the following generalformula:

wherein A-D may be the same or different and may be selected from one ofthe following formulas:

wherein R₁-R₁₁ may be hydrogen and organic groups including alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, cycloalkenyl, substitutedcycloalkenyl, alkynyl, aryl, substituted aryl, arylalkyl, alkylaryl, andalkoxy, where each group preferably contains from 1 carbon atom to about10 carbon atoms, preferably containing from 1 carbon atom to about 6carbon atoms; and wherein x may be CR₁₂ or CR₁₃R₁₄, where R₁₂, R₁₃ andR₁₄ may be hydrogen and organic groups including alkyl, cyclo alkyl,substituted cycloalkyl, alkenyl, cycloalkenyl, substitute cycloalkenyl,alkynyl, aryl, substituted aryl, arylalkyl, alkylaryl, and alkoxy. 6.The composition of matter of claim 5, wherein each of R₁-R₁₄ containsfrom 1 carbon atom to about 10 carbon atoms.
 7. The composition of claim6, wherein each of R₁-R₁₄ contains from 1 carbon atom to about 6 carbonatoms.
 8. The composition of claim 1, wherein the N-heterocylic carbenesubstituted porphyrin is represented by the following formula:

wherein A-D may be the same or different and may be selected from one ofthe following formulas:

wherein R₁-R₁₁ may be hydrogen and organic groups including alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, cycloalkenyl, substitutedcycloalkenyl, alkynyl, aryl, substituted aryl, arylalkyl, alkylaryl, andalkoxy, where each group preferably contains from 1 carbon atom to about10 carbon atoms, preferably containing from 1 carbon atom to about 6carbon atoms; and wherein x may be CR₁₂ or CR₁₃R₁₄, where R₁₂, R₁₃ andR₁₄ may be hydrogen and organic groups including alkyl, cyclo alkyl,substituted cycloalkyl, alkenyl, cycloalkenyl, substitute cycloalkenyl,alkynyl, aryl, substituted aryl, arylalkyl, alkylaryl, and alkoxy. 9.The composition of matter of claim 8, wherein each of R₁-R₁₄ containsfrom 1 carbon atom to about 10 carbon atoms.
 10. The composition ofclaim 9, wherein each of R₁-R₁₄ contains from 1 carbon atom to about 6carbon atoms.
 11. The composition of claim 1, wherein the N-heterocyliccarbene substituted porphyrin is represented by the following formula:

wherein A-D may be the same or different and may be selected from one ofthe following formulas:

wherein R₁-R₁₁ may be hydrogen and organic groups including alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, cycloalkenyl, substitutedcycloalkenyl, alkynyl, aryl, substituted aryl, arylalkyl, alkylaryl, andalkoxy, where each group preferably contains from 1 carbon atom to about10 carbon atoms, preferably containing from 1 carbon atom to about 6carbon atoms; and wherein x may be CR₁₂ or CR₁₃R₁₄, where R₁₂, R₁₃ andR₁₄ may be hydrogen and organic groups including alkyl, cyclo alkyl,substituted cycloalkyl, alkenyl, cycloalkenyl, substitute cycloalkenyl,alkynyl, aryl, substituted aryl, arylalkyl, alkylaryl, and alkoxy. 12.The composition of matter of claim 11, wherein each of R₁-R₁₄ containsfrom 1 carbon atom to about 10 carbon atoms.
 13. The composition ofclaim 12, wherein each of R₁-R₁₄ contains from 1 carbon atom to about 6carbon atoms.
 14. A metal complex comprising: a N-heterocylic carbenesubstituted porphyrin; and at least one metal atom bonded toN-heterocylic carbene substituted porphyrin.
 15. The metal complex ofclaim 14, wherein said metal complex has the following general formula:

wherein A-D may be the same or different and may be selected from one ofthe following formulas:

wherein R₁-R₁₁ may be hydrogen and organic groups including alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, cycloalkenyl, substitutedcycloalkenyl, alkynyl, aryl, substituted aryl, arylalkyl, alkylaryl, andalkoxy, where each group preferably contains from 1 carbon atom to about10 carbon atoms, preferably containing from 1 carbon atom to about 6carbon atoms; wherein x may be CR₁₂ or CR₁₃R₁₄, where R₁₂, R₁₃ and R₁₄may be hydrogen and organic groups including alkyl, cyclo alkyl,substituted cycloalkyl, alkenyl, cycloalkenyl, substitute cycloalkenyl,alkynyl, aryl, substituted aryl, arylalkyl, alkylaryl, and alkoxy; andwhere M is a metal.
 16. The metal complex of claim 15, wherein each ofR₁-R₁₄ contains from 1 carbon atom to about 10 carbon atoms.
 17. Themetal copmlex of claim 16, wherein each of R₁-R₁₄ contains from 1 carbonatom to about 6 carbon atoms.
 18. The metal complex of claim 14, whereinsaid metal atom is selected from the group consisting of IIA metals,group IIA metals, group IIIA metals, group IVA metals, group VA metals,group VIA metals, group VIIA metals, and group VIIIA metals, group IVBmetals, group VB metals, group VIB metals, VIIB metals, lanthanides andactinides.
 19. The metal complex of claim 18, wherein the group IVBmetals are selected from the group consisting of Si, Ge, SN and Pb. 20.The metal complex of claim 18, wherein the group VIB metals are selectedfrom the group consisting of Te and Po.
 21. The metal complex of claim18, wherein rhe group VB metals are selected from the group consistingof P, As, Sb and Bi.
 22. The metal complex of claim 18, wherein thegroup VIIB metal is At.
 23. The metal complex of claim 18, wherein themetal atom is Ag.
 24. The metal complex of claim 18, wherein the metalatom is Gd.
 25. The metal complex of claim 14, wherein saidN-heterocylic carbene substituted porphyrin has the following generalformula:

wherein A-D may be the same or different and may be selected from one ofthe following formulas:

wherein R₁-R₁₁ may be hydrogen and organic groups including alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, cycloalkenyl, substitutedcycloalkenyl, alkynyl, aryl, substituted aryl, arylalkyl, alkylaryl, andalkoxy, where each group preferably contains from 1 carbon atom to about10 carbon atoms, preferably containing from 1 carbon atom to about 6carbon atoms; wherein x may be CR₁₂ or CR₁₃R₁₄, where R₁₂, R₁₃ and R₁₄may be hydrogen and organic groups including alkyl, cyclo alkyl,substituted cycloalkyl, alkenyl, cycloalkenyl, substitute cycloalkenyl,alkynyl, aryl, substituted aryl, arylalkyl, alkylaryl, and alkoxy; andwherein M is a metal.
 26. The composition of matter of claim 25, whereineach of R₁-R₁₄ contains from 1 carbon atom to about 10 carbon atoms. 27.The composition of claim 26, wherein each of R₁-R₁₄ contains from 1carbon atom to about 6 carbon atoms.
 28. The metal complex of claim 25,wherein said metal atom is selected from the group consisting of IIAmetals, group IIA metals, group IIIA metals, group IVA metals, group VAmetals, group VIA metals, group VIIA metals, and group VIIIA metals,group IVB metals, group VB metals, group VIB metals, VIIB metals,lanthanides and actinides.
 29. The metal complex of claim 28, whereinthe group IVB metals are selected from the group consisting of Si, Ge,SN and Pb.
 30. The metal complex of claim 28, wherein the group VIBmetals are selected from the group consisting of Te and Po.
 31. Themetal complex of claim 28, wherein rhe group VB metals are selected fromthe group consisting of P, As, Sb and Bi.
 32. The metal complex of claim28, wherein the group VIIB metal is At.
 33. The metal complex of claim28, wherein the metal atom is Ag.
 34. The metal complex of claim 28,wherein the metal atom is Gd.
 35. The metal complex of claim 14, whereinthe N-heterocylic carbene substituted porphyrin is represented by thefollowing formula:

wherein A-D may be the same or different and may be selected from one ofthe following formulas:

wherein R₁-R₁₁ may be hydrogen and organic groups including alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, cycloalkenyl, substitutedcycloalkenyl, alkynyl, aryl, substituted aryl, arylalkyl, alkylaryl, andalkoxy, where each group preferably contains from 1 carbon atom to about10 carbon atoms, preferably containing from 1 carbon atom to about 6carbon atoms; wherein x may be CR₁₂ or CR₁₃R₁₄, where R₁₂, R₁₃ and R₁₄may be hydrogen and organic groups including alkyl, cyclo alkyl,substituted cycloalkyl, alkenyl, cycloalkenyl, substitute cycloalkenyl,alkynyl, aryl, substituted aryl, arylalkyl, alkylaryl, and alkoxy; andwherein M is a metal.
 36. The metal complex of claim 35, wherein each ofR₁-R₁₄ contains from 1 carbon atom to about 10 carbon atoms.
 37. Themetal complex of claim 36, wherein each of R₁-R₁₄ contains from 1 carbonatom to about 6 carbon atoms.
 38. The metal complex of claim 35, whereinsaid metal atom is selected from the group consisting of IIA metals,group IIA metals, group IIIA metals, group IVA metals, group VA metals,group VIA metals, group VIIA metals, and group VIIIA metals, group IVBmetals, group VB metals, group VIB metals, VIIB metals, lanthanides andactinides.
 39. The metal complex of claim 35, wherein the group IVBmetals are selected from the group consisting of Si, Ge, SN and Pb. 40.The metal complex of claim 35, wherein the group VIB metals are selectedfrom the group consisting of Te and Po.
 41. The metal complex of claim35, wherein rhe group VB metals are selected from the group consistingof P, As, Sb and Bi.
 42. The metal complex of claim 35, wherein thegroup VIIB metal is At.
 43. The metal complex of claim 35, wherein themetal atom is Ag.
 44. The metal complex of claim 35, wherein the metalatom is Gd.
 45. The metal complex of claim 14, wherein the N-heterocyliccarbene substituted porphyrin is represented by the following formula:

wherein A-D may be the same or different and may be selected from one ofthe following formulas:

wherein R₁-R₁₁ may be hydrogen and organic groups including alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, cycloalkenyl, substitutedcycloalkenyl, alkynyl, aryl, substituted aryl, arylalkyl, alkylaryl, andalkoxy, where each group preferably contains from 1 carbon atom to about10 carbon atoms, preferably containing from 1 carbon atom to about 6carbon atoms; wherein x may be CR₁₂ or CR₁₃R₁₄, where R₁₂, R₁₃ and R₁₄may be hydrogen and organic groups including alkyl, cyclo alkyl,substituted cycloalkyl, alkenyl, cycloalkenyl, substitute cycloalkenyl,alkynyl, aryl, substituted aryl, arylalkyl, alkylaryl, and alkoxy; andwherein M is a metal.
 46. The metal complex of claim 45, wherein each ofR₁-R₁₄ contains from 1 carbon atom to about 10 carbon atoms.
 47. Themetal complex of claim 45, wherein each of R₁-R₁₄ contains from 1 carbonatom to about 6 carbon atoms.
 48. The metal complex of claim 45, whereinsaid metal atom is selected from the group consisting of IIA metals,group IIA metals, group IIIA metals, group IVA metals, group VA metals,group VIA metals, group VIIA metals, and group VIIIA metals, group IVBmetals, group VB metals, group VIB metals, VIIB metals, lanthanides andactinides.
 49. The metal complex of claim 46, wherein the group IVBmetals are selected from the group consisting of Si, Ge, SN and Pb. 50.The metal complex of claim 46, wherein the group VIB metals are selectedfrom the group consisting of Te and Po.
 51. The metal complex of claim46, wherein rhe group VB metals are selected from the group consistingof P, As, Sb and Bi.
 52. The metal complex of claim 46, wherein thegroup VIIB metal is At.
 53. The metal complex of claim 46, wherein themetal atom is Ag.
 54. The metal complex of claim 46, wherein the metalatom is Gd.
 55. A composition of matter comprising: a N-heterocyliccarbene substituted porphyrin; at least one metal atom bonded to saidN-heterocylic carbene substituted porphyrin; and a targeting moietybonded to said N-heterocylic carbene substituted porphyrin.
 56. Thecomposition of matter of claim 55, wherein wherein said N-heterocyliccarbene substituted porphyrin has the following general formula:

wherein A-D may be the same or different and may be selected from one ofthe following formulas:

wherein R₁-R₁₁ may be hydrogen and organic groups including alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, cycloalkenyl, substitutedcycloalkenyl, alkynyl, aryl, substituted aryl, arylalkyl, alkylaryl, andalkoxy, where each group preferably contains from 1 carbon atom to about10 carbon atoms, preferably containing from 1 carbon atom to about 6carbon atoms; and wherein x may be CR₁₂ or CR₁₃R₁₄, where R₁₂, R₁₃ andR₁₄ may be hydrogen and organic groups including alkyl, cyclo alkyl,substituted cycloalkyl, alkenyl, cycloalkenyl, substitute cycloalkenyl,alkynyl, aryl, substituted aryl, arylalkyl, alkylaryl, and alkoxy. 57.The composition of matter of claim 56, wherein each of R₁-R₁₄ containsfrom 1 carbon atom to about 10 carbon atoms.
 58. The composition ofmatter of claim 57, wherein each of R₁-R₁₄ contains from 1 carbon atomto about 6 carbon atoms.
 59. The composition of matter of claim 56,wherein said metal atom is selected from the group consisting of IIAmetals, group IIA metals, group IIIA metals, group IVA metals, group VAmetals, group VIA metals, group VIIA metals, and group VIIIA metals,group IVB metals, group VB metals, group VIB metals, VIIB metals,lanthanides and actinides.
 60. The composition of matter of claim 59,wherein the group IVB metals are selected from the group consisting ofSi, Ge, SN and Pb.
 61. The composition of matter of claim 59, whereinthe group VIB metals are selected from the group consisting of Te andPo.
 62. The composition of matter of claim 59, wherein rhe group VBmetals are selected from the group consisting of P, As, Sb and Bi. 63.The composition of matter of claim 59, wherein the group VIIB metal isAt.
 64. The composition of matter of claim 59, wherein the metal atom isAg.
 65. The composition of matter of claim 59, wherein the metal atom isGd.
 66. The composition of matter of claim 55, wherein saidN-heterocylic carbene substituted porphyrin has the following generalformula:

wherein A-D may be the same or different and may be selected from one ofthe following formulas:

wherein R₁-R₁₁ may be hydrogen and organic groups including alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, cycloalkenyl, substitutedcycloalkenyl, alkynyl, aryl, substituted aryl, arylalkyl, alkylaryl, andalkoxy, where each group preferably contains from 1 carbon atom to about10 carbon atoms, preferably containing from 1 carbon atom to about 6carbon atoms; and wherein x may be CR₁₂ or CR₁₃R₁₄, where R₁₂, R₁₃ andR₁₄ may be hydrogen and organic groups including alkyl, cyclo alkyl,substituted cycloalkyl, alkenyl, cycloalkenyl, substitute cycloalkenyl,alkynyl, aryl, substituted aryl, arylalkyl, alkylaryl, and alkoxy. 67.The composition of matter of claim 66, wherein each of R₁-R₁₄ containsfrom 1 carbon atom to about 10 carbon atoms.
 68. The composition ofmatter of claim 67, wherein each of R₁-R₁₄ contains from 1 carbon atomto about 6 carbon atoms.
 69. The composition of matter of claim 66,wherein said metal atom is selected from the group consisting of IIAmetals, group IIA metals, group IIIA metals, group IVA metals, group VAmetals, group VIA metals, group VIIA metals, and group VIIIA metals,group IVB metals, group VB metals, group VIB metals, VIIB metals,lanthanides and actinides.
 70. The composition of matter of claim 69,wherein the group IVB metals are selected from the group consisting ofSi, Ge, SN and Pb.
 71. The composition of matter of claim 69, whereinthe group VIB metals are selected from the group consisting of Te andPo.
 72. The composition of matter of claim 69, wherein rhe group VBmetals are selected from the group consisting of P, As, Sb and Bi. 73.The composition of matter of claim 69, wherein the group VIIB metal isAt.
 74. The composition of matter of claim 69, wherein the metal atom isAg.
 75. The composition of matter of claim 69, wherein the metal atom isGd.
 76. The composition of matter of claim 55, wherein the N-heterocyliccarbene substituted porphyrin is represented by the following formula:

wherein A-D may be the same or different and may be selected from one ofthe following formulas:

wherein R₁-R₁₁ may be hydrogen and organic groups including alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, cycloalkenyl, substitutedcycloalkenyl, alkynyl, aryl, substituted aryl, arylalkyl, alkylaryl, andalkoxy, where each group preferably contains from 1 carbon atom to about10 carbon atoms, preferably containing from 1 carbon atom to about 6carbon atoms; and wherein x may be CR₁₂ or CR₁₃R₁₄, where R₁₂, R₁₃ andR₁₄ may be hydrogen and organic groups including alkyl, cyclo alkyl,substituted cycloalkyl, alkenyl, cycloalkenyl, substitute cycloalkenyl,alkynyl, aryl, substituted aryl, arylalkyl, alkylaryl, and alkoxy. 77.The composition of matter of claim 76, wherein each of R₁-R₁₄ containsfrom 1 carbon atom to about 10 carbon atoms.
 78. The composition ofmatter of claim 77, wherein each of R₁-R₁₄ contains from 1 carbon atomto about 6 carbon atoms.
 79. The composition of matter of claim 76,wherein said metal atom is selected from the group consisting of IIAmetals, group IIA metals, group IIIA metals, group IVA metals, group VAmetals, group VIA metals, group VIIA metals, and group VIIIA metals,group IVB metals, group VB metals, group VIB metals, VIIB metals,lanthanides and actinides.
 80. The composition of matter of claim 79,wherein the group IVB metals are selected from the group consisting ofSi, Ge, SN and Pb.
 81. The composition of matter of claim 79, whereinthe group VIB metals are selected from the group consisting of Te andPo.
 82. The composition of matter of claim 79, wherein rhe group VBmetals are selected from the group consisting of P, As, Sb and Bi. 83.The composition of matter of claim 79, wherein the group VIIB metal isAt.
 84. The composition of matter of claim 79, wherein the metal atom isAg.
 85. The composition of matter of claim 79, wherein the metal atom isGd.
 86. The composition of matter of claim 55, wherein the N-heterocyliccarbene substituted porphyrin is represented by the following formula:

wherein A-D may be the same or different and may be selected from one ofthe following formulas:

wherein R₁-R₁₁ may be hydrogen and organic groups including alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, cycloalkenyl, substitutedcycloalkenyl, alkynyl, aryl, substituted aryl, arylalkyl, alkylaryl, andalkoxy, where each group preferably contains from 1 carbon atom to about10 carbon atoms, preferably containing from 1 carbon atom to about 6carbon atoms; and wherein x may be CR₁₂ or CR₁₃R₁₄, where R₁₂, R₁₃ andR₁₄ may be hydrogen and organic groups including alkyl, cyclo alkyl,substituted cycloalkyl, alkenyl, cycloalkenyl, substitute cycloalkenyl,alkynyl, aryl, substituted aryl, arylalkyl, alkylaryl, and alkoxy. 87.The composition of matter of claim 86, wherein each of R₁-R₁₄ containsfrom 1 carbon atom to about 10 carbon atoms.
 88. The composition ofmatter of claim 87, wherein each of R₁-R₁₄ contains from 1 carbon atomto about 6 carbon atoms.
 89. The composition of matter of claim 86,wherein said metal atom is selected from the group consisting of IIAmetals, group IIA metals, group IIIA metals, group IVA metals, group VAmetals, group VIA metals, group VIIA metals, and group VIIIA metals,group IVB metals, group VB metals, group VIB metals, VIIB metals,lanthanides and actinides.
 90. The composition of matter of claim 89,wherein the group IVB metals are selected from the group consisting ofSi, Ge, SN and Pb.
 91. The composition of matter of claim 89, whereinthe group VIB metals are selected from the group consisting of Te andPo.
 92. The composition of matter of claim 89, wherein rhe group VBmetals are selected from the group consisting of P, As, Sb and Bi. 93.The composition of matter of claim 89, wherein the group VIIB metal isAt.
 94. The composition of matter of claim 89, wherein the metal atom isAg.
 95. The composition of matter of claim 89, wherein the metal atom isGd.
 96. The composition of claim 55, wherein the targeting moiety isselected form the group consisting of biotin and nitroimidazoles. 97.The composition of claim 55, wherein said linker is selected from thegroup consisting of alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl,arylalkyl, alkylaryl, alkoxy, amines, amides, and polyethers.